Certain 4-/(indazol-3-yl)-pyridinium/compounds

ABSTRACT

Quaternary pyridinium salts are prepared by quaternizing the corresponding pyridine compounds which in turn are prepared by various methods. The quaternary salts are useful for lowering blood glucose in warm-blooded animals.

United States Patent Bauer et al. [4 July 18, 1972 [54] CERTAIN 4-/(INDAZOL-3-YL)- [56] References Cited P CO UNITED STATES PATENTS Z l [72] v i N I 3,574,842 4/1971 Bauer et al ..260/296 R lium Joseph Fanshawe, Gretchen Ellen w g both of Pearl River, N Y 3,598,829 l0/l97l Bauer et a]. ..260/296 R [73] Assignee: American Cyanamid Company, Stamford, P i E i -Al R t Conn. Attorney-Ernest Y. Miller 2 F'] d: Se 1. 8 1970 [2 l e p 57 ABSTRACT [21] Appl. No.: 70,573

Quaternary pyndlmum salts are prepared by quaternlzlng the corresponding pyridine compounds which in turn are US. Cl. B, B, repared various The quaternary salts are useful [51 1 Int. Cl- ..C07d for lowering glucose in wm.b|oded animals [58] Field of Search ..260/296 B 3 Claims, No Drawings 1 2 CERTAIN 4-/(lNDAZOL-3-YL)- The intermediate pyridine bases before quaternization are PYRlDlNIUM/COMPOUNDS novel compounds and are considered to be a pan of the DESCRIPTION OF THE INVENTION present invention. They may be illustrated by the following formula: This invention relates to new organic compoundsfmore par- 5 ticularly, it relates to quaternary p'yridinium 'salts, intermediates for preparation of the salts, and methods of preparing the same.

The new compounds of the present invention may be illustrated by the following formula:

wherein Z is as defined above.

x- Among the compounds of the present invention are, for example: 4-(4-pyridyl)indazole, 3-(4-pyridyl)-l,2-benzisox- Z l 5 azole, 3-(4-pyridyl)benzofuran, l-methyl-4-( 3-indazolyl)p'yridinium iodide, l-propyl 4-(3-indazolyl)pyridinium bromide, l-methyl-4-( 1,2-benzisoxazol-3-yl )pyridinium wherein R is lower allcyl; Z is a trivalent radical selected from iodide, l-ethyl-4-( l ,2-benzisoxazol-3-yl)pyridinium chloride,

the group consisting of l-methyl-4-( 3-benzofuranyl)-pyridinium chloride, l-butyl-4- 2 (3-benzofuranyl)pyridinium bromide, and the like.

H IL IQ The compounds of the present invention show N, I, hypoglycemic activity based on the following data which shows a reduction of the blood sugar levels in warm-blooded H animals such as mice. When the compounds are administered orally to normal mice, a reduction of blood sugar levels is oband X is a monovalent pharmaceutically acceptable anion. ed; Mi di h di are CF21 ca nh Farms Lower alkyl groups are those having one to four carbons such 25-30 g a The quaternary salts f hi invention are das p methyl, elhyl, P PYL P PYL l ministered by gavage as 0.5 percent carboxymethylcellulose y MOmValem Pharmaceutical! acceptable anions suspensions; control animals receive an equivalent volume of dude chloride bromide icdidei fluoride vehicle. Foodis withheld from animals after dosing. Blood glu- The f q'f of the f" 'f P y Prepared cose is determined 5 hours after dosing, on blood samples obby quatermzauon of an a'ppmpnate Pyndme base wlth for tained from the retrobulbar plexuses of mice, by the method 'P 3 "9 alky' hallde a temperature 0 of Hoffman 1. Biol. Chem., 120, 51 1937 as adapted to the "F a f such as alcohol l a i of Technicon AutoAnalyzer and is expressed as percent change mlmne f m open vessel or a 9 The from predose values. The testing data is summarized in Table desired Pyndyhndazole prepared by dehydmgenauo" of the I. Comparable data for the antidiabetic drugs phenformin and known tetrahydro-compound. The requisite pyridylbenzisoxtolbutamide are also pr8em azole is prepared by reaction of hydroxylamine and ochlorophenyl pyridyl ketone. The requisite pyridylbenzofuran TABLE] is prepared by reaction of a benzofuranone with pyridyllithi- 40 urn, followed by dehydration of the intermediate alcohol. Decrease. f B f Glucose In After oral These reactions are illustrated schematically immediately Administration of Quaternary Pyn nlum alts below: Hours Percent Dose afier Decrease in I Compound mmols/kg. dosing Blood Glucose N RX N I l-Methyl-4-(3-indazolyl)- 1.5 s 54 :4 Z Z pyridinuum Iodide l-Methyl-4-( l,2-benziso- 3.0 5 63 I l l xaz ol-3-yl)pyridinium 11 Iodide I l-Methyl-4-( J-benzofur- 0.5 5 5 2 .t 5 anyl)pyridinium Iodide Phenformin 1.6 5 49 1 6 Tolbutamide 3.0 5 4i i 5 Ill These results show that the compounds of the present invention are useful, as are tolbutamide and phenformin, in the lowering of blood glucose levels in warm-blooded animals. W Their efiectiveness is comparable to that seen with phenformin and tolbutamide. The present compounds may be orally administered at a dose of 1 mg. to 200 mg. per kg. of body weight per day.

SPECIFIC DISCLOSURE v The preparation of the compounds of this invention will be OH H o described in greater detail in conjunction with the following lg, examples.

EXAMPLE 1 Preparation of 3-(4-Pyridyl)indazole A stirred mixture of 1.0 g'. of 3-(4-pyridyl)-4,5,6,7- wherein R, Z and X are as defined above. tetrahydroindazole [J. Med. Chem., 11, 981 (1968)], 0.2 g. of

10 percent palladium-on-carbon, and 40 ml. of diphenyl ether is heated under reflux under nitrogen for 7 hours, filtered, diluted with chloroform, and extracted with 6N hydrochloric acid. The aqueous phase is made basic with sodium hydroxide and extracted with chloroform. The chloroform solution is dried and concentrated to a solid. Recrystallization from acetonitrile provides offwhite crystals, melting point 174-l 80 C.

EXAMPLE 2 Preparation of 1-Methyl-4-( 3-indazolyl)pyridinium Iodide A solution of 2.0 g. of 3-( 4-pyridyl)indazole, ml. of methyl iodide, and 30 ml. of ethanol is heated under reflux for 2 hours, cooled, and filtered. The collected solid is recrystallized from methanol to provide yellow crystals, melting point 275-278 C.

EXAMPLE 3 Preparation of 3-(4-Pyridyl)-1,2-benzisoxazole To a stirred solution of 6.4 g. of 4-(o-chlorobenzoyl)- pyridine, 4.4 g. of hydroxylamine hydrochloride, 100 ml. of methyl cellosolve, and 60 ml. of water is added a solution of 18.5 g. of potassium hydroxide in 40 ml. of water. The solution is heated under reflux for hours, cooled, diluted with water, and filtered. The collected solid is washed with water and dried to provide off-white solid, melting point 74-76 C.

EXAMPLE 4 Preparation of 1-Methyl-4-(1,2-benzisoxazol-3-yl)pyridinium iodide A solution of 1.2 g. of 3-(4-pyridyl)-1,2-benzisoxazole, 3.65 g. of methyl iodide, and 3.6 ml. of dimethylfonnamide is warmed briefly on a steam bath, cooled, diluted with ether, and filtered. The collected solid is dissolved in methanol and reprecipitated with ether to provide an orange solid, melting point 267269 C., dec.

EXAMPLE 5 EXAMPLE 6 Preparation of 3-(4-Pyridyl)benzofuran A mixture of 0.42 g. of 2,3-dihydro-3-(4-pyridyl)-4- benzofuranol and 0.1 g. of potassium bisulfate is fused at 190 C. for minutes, cooled, diluted with excess aqueous sodium hydroxide, and extracted with chloroform. The chloroform solution is dried and concentrated to a yellow oil. The product forms a crystalline hydrochloride salt, melting point 210-21 1 C.

EXAMPLE 7 Preparation of l-Methyl-4-(3-benzofuranyl)pyridinium iodide A solution of 3.0 g. of 3-(4-pyridyl)benzofuran, 10 ml. of methyl iodide, and 35 ml. of ethanol is heated under reflux for 30 minutes, cooled, diluted with ether, and filtered. Recrystallization of the collected solid from ethanol gives yellow crystals, melting point 24l-243 C.

EXAMPLE 8 Preparation of 50 mg. Tablets 1-methyl-4-( 1,2-benzisoxazol- 250.0 g

3-y1)pyridinium iodide Lactose 400. g

Com Starch (For mix) 50. g

Corn Starch (For paste) 37.5 g

Magnesium stearate 1%) 7.5 g. 745.0 g.

The active ingredient, lactose and corn starch (for mix) are blended together. The corn starch (for paste) is suspended in 300 ml. of water, and heated with stirring, to form a paste. This paste is then used to granulate the mixed powders. Additional water is sued, if necessary. The wet granules are passed through a No. 8 hand screen and dried at 120 F. The dry granules are passed through a No. 16 screen. The mixture is lubricated with 1 percent magnesium stearate and compressed into tablets in a suitable tableting machine.

EXAMPLE 9 Preparation of 25 mg. Capsules For 10,000 Capsule 1-methyl-4-(3-indazolyl)- 250.0 g. pyridinium iodide Lactose, U.S.P. 5000 g. Magnesium Stearate (0.5%) 350.0 g. total: 5600 g.

The formulation is thoroughly mixed and placed as equal quantities in 10,000 hard shell capsules or soft shell capsules. Each capsule contains 25 mg. of drug.

EXAMPLE 10 Preparation of drug solution l-methyl-4-(3-benzofuranyl)- 5 g.

pyridinium iodide Sodium carboxymethylcellulose 5% cc.

aqueous solution q.s.

The above solution contains approximately 50 mg. per cc. of finished product.

We claim:

1. A pyridine compound of the formula:

wherein R is lower alkyl and X is a monovalent pharmaceutically acceptable anion.

2. The pyridine compound in accordance with claim 1, 1- methyl-4-( 3-indazolyl )pyridinium iodide.

3. The pyridine compound in accordance with claim 1, 3- (4-pyridy1)indazole.

l l 4' t l 

2. The pyridine compound in accordance with claim 1, 1-methyl-4-(3-indazolyl)pyridinium iodide.
 3. The pyridine compound in accordance with claim 1, 3-(4-pyridyl)indazole. 